The goal of these studies is to increase our understanding of the nature of the glucocorticoid resistance that develops in patients with acute and chronic lymphocytic leukemia. Lymphocytes obtained from such patients during various phases of treatment will be tested: (a) for the presence of cytoplasmic and nuclear glucocorticoid receptors; (b) for the ability of the cytoplasmic hormone-receptor complex to undergo cytoplasmic-nuclear transformations in the intact cells; (c) for the presence of nuclear acceptor sites for glucocorticoid-receptor complexes in nuclei isolated from these cells, using glucocorticoid-receptor complexes from various sources including rat thymus cells; (d) for response to various conditions affecting glucocorticoids, as expressed in reduced glucose uptake, increased nuclear fragility, and survival after long-term incubation. These lymphocyte populations will also be studied immunologically for T-cell, B-cell and other characteristics through tests for: (a) presence of immunoglobulins; (b) rosette formation; (c) receptors for antibody and complement: (d) response to mitogens. In parallel work, control of glucocorticoid receptors will be studied with rat thymus cells (in short and long-term incubations as well as in vivo) to determine: (a) the kinetics of disappearance and reappearance of cytoplasmic and nuclear glucocorticoid receptors on treatment with hormone, with blockers of protein synthesis such as cycloheximide, and with conditions such as anaerobiosis that lower ATP levels; (b) the effects of the latter two treatments on nuclear acceptor sites; (c) the mechanisms of appearance and disappearance of receptors: e.g. are receptors phosphorylated and dephosphorylated? Are there cofactors or enzymes involved? Does loss of receptor binding mean loss or transformation of receptor protein? (d) the mechanism of the sudden appearance of glucocorticoid receptors in the thymus of neonatal rats. Significant findings with rat lymphocytes will be immediatedly applied to the work with human leukemic lymphocytes, and vice versa. BIBLIOGRAPHIC REFERENCE: A. Munck, R. Foley. Kinetics of glucocorticoid-receptor complexes in rat thymus cells. J. Steroid Biochem. 7, 1117-1122 (1976).